title: Novel fentanyl-based dual μ/δ-opioid agonists for the treatment of acute and chronic pain.
abstract: Approximately one third of the adult U.S. population suffers from some type of on-going, chronic pain annually, and many more will have some type of acute pain associated with trauma or surgery. First-line therapies for moderate to severe pain include prescriptions for common mu opioid receptor agonists such as morphine and its various derivatives. The epidemic use, misuse and diversion of prescription opioids have highlighted just one of the adverse effects of mu opioid analgesics. Alternative approaches include novel opioids that target delta or kappa opioid receptors, or compounds that interact with two or more of the opioid receptors.
  
  
  OBJECTIVE
  Here we report the pharmacology of a newly synthesized bifunctional opioid agonist (RV-Jim-C3) derived from combined structures of fentanyl and enkephalin in rodents. RV-Jim-C3 has high affinity binding to both mu and delta opioid receptors.
  
  
  METHODS
  Mice and rats were used to test RV-Jim-C3 in a tailflick test with and without opioid selective antagonist for antinociception. RV-Jim-C3 was tested for anti-inflammatory and antihypersensitivity effects in a model of formalin-induced flinching and spinal nerve ligation. To rule out motor impairment, rotarod was tested in rats.
  
  
  RESULTS
  RV-Jim-C3 demonstrates potent-efficacious activity in several in vivo pain models including inflammatory pain, antihyperalgesia and antiallodynic with no significant motor impairment.
  
  
  CONCLUSIONS
  This is the first report of a fentanyl-based structure with delta and mu opioid receptor activity that exhibits outstanding antinociceptive efficacy in neuropathic pain, reducing the propensity of unwanted side effects driven by current therapies that are unifunctional mu opioid agonists.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Podolsky
authors.forename: Alexander
authors.initials: A
authors.lastname: Sandweiss
authors.forename: Jackie
authors.initials: J
authors.lastname: Hu
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bilsky
authors.forename: Jim P
authors.initials: JP
authors.lastname: Cain
authors.forename: Vlad K
authors.initials: VK
authors.lastname: Kumirov
authors.forename: Yeon Sun
authors.initials: YS
authors.lastname: Lee
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: Ruben S
authors.initials: RS
authors.lastname: Vardanyan
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
mesh_terms: D059787:Acute Pain / Q000188:drug therapy*; D000701:Analgesics, Opioid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D059350:Chronic Pain / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004745:Enkephalins / Q000737:chemistry / Q000494:pharmacology*; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004745:Enkephalins; D009292:Narcotic Antagonists; C585981:RV-Jim-C3; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009271:Naltrexone; C055382:naltrindole; D005283:Fentanyl
keywords: Allodynia; Chronic pain; Delta opioid; Fentanyl; Formalin flinch; Hyperalgesia; Inflammatory; Mice; Naloxone; Rat; Spinal nerve ligation; mu opioid